An important new model for the study of the inherited genetic component of breast cancer is proposed. This model is based on the WKy rat strain which is almost completely resistant to spontaneous and chemically (e.g. 7,12-dimethylbenz(a)anthracene (DMBA) and N-nitrosomethylurea (NMU)) induced mammary carcinomas. It is hypothesized based on preliminary data that the genetics underlying this resistance to mammary cancer is controlled by interacting dominant resistance and enhancer genes with the resistance gene(s) being epistatic over enhancer gene(s). The goal of this project is to identify and characterize these genes and to positionally clone the major resistance gene (likely to be Mcs-4). The first aim is to genetically identify the quantitative trait loci (QTLs) that control the overall susceptibility of the WKy to DMBA-induced mammary carcinomas. This information will be used in the second aim to breed and characterize two congenic rat strains, each carrying either the major resistance QTL or the major enhancer QTL. Characterization of these congenics includes the determination of whether the resistance/enhancer loci act in a cell autonomous fashion. The congenic rats will also be used in Aim 3 to identify genes that are differentially expressed between the congenic rats and the control WF rat strain. These genes will both provide hypothesis-generating data regarding gene function and an assay to screen candidate breast cancer susceptibility genes. Aim 4 will identify (by a positional cloning approach) and evaluate candidate genes at the resistance locus (likely Mcs-4). Several novel biological assays to evaluate these potential candidates will be used. Screened candidates will be tested using transgenic rat models. Finally, human homologues will be cloned for strong candidate genes in anticipation of future human studies. The accomplishment of our goal may provide: additional insight and reagents to better estimate the genetic risk of women for breast cancer; and new targets for the development of drugs to prevent breast cancer.